EP4262767A1 - Parenteral cannabinoid formulations and uses thereof - Google Patents

Parenteral cannabinoid formulations and uses thereof

Info

Publication number
EP4262767A1
EP4262767A1 EP21911967.4A EP21911967A EP4262767A1 EP 4262767 A1 EP4262767 A1 EP 4262767A1 EP 21911967 A EP21911967 A EP 21911967A EP 4262767 A1 EP4262767 A1 EP 4262767A1
Authority
EP
European Patent Office
Prior art keywords
formulation
cannabinoid
present
cannabidiol
buffering agents
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21911967.4A
Other languages
German (de)
English (en)
French (fr)
Inventor
Brett Jackson Lanier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Isocelles Pharmaceuticals Inc
Original Assignee
Isocelles Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Isocelles Pharmaceuticals Inc filed Critical Isocelles Pharmaceuticals Inc
Publication of EP4262767A1 publication Critical patent/EP4262767A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the worldwide opioid crisis is well known as reported in the media and scientific literature using statistics from well-recognized health agencies such as, for example, the World Health Organization, the United State Centers for Disease Control and the United Stated Department of Health and Human Services.
  • the literature and these agencies report that the initial use of opioids occurs for a variety of reasons and sources, including voluntary use that leads to addiction, legitimate medical reasons are frequently the basis and justification for initial opioid use.
  • the first step in medically justified opioid use, that can lead to longer-term addiction is frequently through the use of parenterally administered opioids for peri- and/or post-operative pain.
  • the pharmaceutical, health, social and medical communities have been searching, generally unsuccessfully, for alternative, effective, safe treatments for peri-operative pain management, including peri- and/or post-operative pain management.
  • the present invention provides certain non-toxic parenteral formulations containing one or more cannabinoid for the treatment, among other medical indications, of peri-operative pain.
  • Cannabinoid parenteral formulations are not commonly described in the scientific and patent literature. Generally, many of the scientific papers describe cannabinoid formulations designed for immediate injection into laboratory animals, without concern for long-term safety and/or stability. One study merely indicated formulating a cannabinoid, cannabidiol (CBD), with or without (-)-trans A 9 -tetrahydrocannabinol, solubilized in “animal fat”. A more pharmaceutically elegant parenterally-administered cannabinoid formulation has been described in U.S. Pat. Pub. 2019/0314296, which also includes a more detailed review of parenteral cannabinoid formulations developed prior to the filing date of June 17, 2017 for this patent publication.
  • the pharmaceutical formulation taught and claimed therein comprises certain key elements: i) a cannabinoid; ii) an isotonic agent; iii) a surfactant; and iv) at least one antioxidant.
  • the isotonic agent is defined as a group consisting of: polyethylene glycol, glycerol, saline, and glucose and are used in amounts to provide an osmolality in the range of, 100-500 mOsMol/Kg, more preferably, 200-400 mOsMol/Kg, more preferably still 285-310 mOsMol/Kg, and most preferably about 300 mOsMol/Kg. Most preferably the isotonic agent is glycerol and is present in an amount of 5 to 50 mg/ml, more preferably 10-30 mg/ml, and most preferably 20 mg/ml.
  • isotonic agents can be problematic and can be, in fact, toxic to a patient, particularly if the patient is also administered maintenance IV fluids.
  • isotonic agents can be problematic and can be, in fact, toxic to a patient, particularly if the patient is also administered maintenance IV fluids.
  • the use of glucose and dextrose as IV fluids vary among countries. Without additional dextrose in a parenteral medicament, which could exacerbate the effect of the administration of IV fluids containing dextrose
  • saline sodium chloride
  • an isotonic agent in a parenteral formulation may render such formulation toxic or, at least, medically problematic, particularly when an IV solution is co-administered.
  • Such coadministration would not be uncommon when an IV is required in addition to peri-operative pain medication.
  • the referenced U.S. Patent Publication does not contain a buffer.
  • pH of the administered medicament can vary and, at a likely pH of about 4.0, the patient is likely to suffer from site irritation and additional pain.
  • a buffered cannabinoid pharmaceutical formulation would be more tolerable for the patient.
  • a buffered cannabinoid parenteral formulation provides the attending physician with a known solution, particularly when other fluids and/or parenteral treatments are being administered and could be impacted by the administration, particularly by infusion, of a composition of the present invention.
  • the present invention provides a non-toxic, pharmaceutically acceptable, stable parenteral cannabinoid formulation used for, among other uses, the treatment of peri-operative pain.
  • One aspect of the present invention provides a non-toxic parenteral pharmaceutical formulation comprising: i. at least one cannabinoid; ii. at least one surfactant; iii. at least one antioxidant; and iv. at least one chelating agent; and v. optionally, at least one buffering agent selected from the group consisting of hypotonic buffering agents and a hypertonic buffering agents.
  • Another aspect of the present invention provides a non-toxic parenteral pharmaceutical formulation comprising: i. at least one cannabinoid; ii. at least one surfactant; iii. at least one antioxidant and iv. at least one chelating agent; and v. optionally, at least one buffering agent selected from the group consisting of hypotonic buffering agents and a hypertonic buffering agents; providing an isotonic agent is not added to the formulation.
  • Each of the elements or constituents of the present invention are pharmaceutically acceptable.
  • cannabinoid is selected from the group consisting of at least one plant-derived cannabinoid and a synthetic cannabinoid.
  • a further aspect provides for the formulations described above which contains not more that 0.3% (-)-trans A 9 -tetrahydrocannabinol.
  • Another aspect provides for the formulations described above which is devoid of (-)-trans A 9 - tetrahy drocannabinol .
  • THC tetrahydrocannabinol
  • a further aspect provides the formulations described above having a shelf-life of at least twelve months without refrigeration.
  • An additional aspect is a formulation of the present invention that can be terminally sterilized.
  • Another aspect provides a method of preparing a formulation of the present invention comprising: i. combining at least one surfactant with an at least one antioxidant and at least one cannabinoid to a first vessel; ii. combining at least one of the same or different second antioxidant and at least one chelating agent to a second vessel; and iii. combining the contents of the first and second vessels; and iv. optionally adding at least one buffering agent selected from the group consisting of hypotonic buffering agents and hypertonic buffering agents.
  • Another aspect of the present invention provides a method of preparing a formulation of the present invention comprising: i. combining at least one surfactant with an at least one antioxidant and at least one cannabinoid to a first vessel; ii. combining at least one of the same or different second antioxidant and at least one chelating agent to a second vessel; and iii. combining the contents of the first and second vessels; and iv. optionally adding at least one buffering agent selected from the group consisting of hypotonic buffering agents and hypertonic buffering agents; providing an isotonic agent is not added to the formulation.
  • cannabinoid is selected from the group consisting of a plant-derived cannabinoid and a synthetic cannabinoid.
  • a further aspect provides for the method described above wherein the formulation contains not more that 0.3% (-)-trans A 9 -tetrahydrocannabinol.
  • Another aspect provides for the method described above wherein the formulation is devoid of (-)-trans A 9 -tetrahydrocannabinol .
  • THC tetrahydrocannabinol
  • a further aspect provides for a method of treating a mammal in need of treatment comprising parenteral administration, typically intravenous administration, of a composition of the present invention.
  • parenteral administration typically intravenous administration
  • the mammal being treated is a human.
  • the present invention also provides a method of treating a mammal in need of treatment for pain selected from the group consisting of peri-operative, post-operative pain and combinations thereof comprising parenteral administration, typically intravenous administration, of a formulation of the present invention.
  • active pharmaceutical ingredient means a substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient in the drug product.
  • acute pain means pain that has a sudden onset and commonly declines over a short time (days, hours, minutes) and may follow injury to the body and/or surgery, and which generally disappears when the bodily injury/surgical wound heals.
  • antioxidant has the meaning typically used in the pharmaceutical formulation arts. Exemplary anti-oxidants are described further herein.
  • buffering agent means a weak acid or base, typically a base as used herein, used to maintain the acidity (pH) of a solution near a chosen value after the addition of another acid or base. That is, the function of a buffering agent is to prevent a rapid change in pH when acids or bases are added to the solution. Exemplary buffering agents are described further herein.
  • cannabinoid means the any of a group of closely related compounds which includes, for example and without limitation, cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerolpropyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA) and other active constituents of the cannabis plant including, for example, each of the phytocannabinoids.
  • CBC cannabichromene
  • CBCV cannabichro
  • bioactive constituents include, for example and without limitation, cannabidiol-Cl (CBD-Cl ); cannabidiol-C4 (CBD-C4); and cannabidiol-C6 (CBD-C6).
  • bioactive metabolites such as, without limitation, 7-hydroxy CBD.
  • Such compounds and constituents can be derived from the cannabis plant or synthetically prepared.
  • chelating agent has the meaning typically used in the pharmaceutical formulation arts. Exemplary chelating agents are described further herein.
  • chronic pain means pain that persists past normal healing time and lacks the acute warning function of physiological nociception. Usually, pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months
  • drug form refers to one or more vials, ampules, syringes, infusion bag or other pharmaceutically acceptable container filled with a pharmaceutical formulation solution of the present invention.
  • peri-operative pain refers to pain before, during, and or/after a surgical procedure.
  • peri-operative pain management refers to actions before, during, and/or after a surgical procedure that are intended to reduce or eliminate postoperative pain before the patient is discharged after the procedure.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition or formulation that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use as well as veterinary use.
  • surfactant has the meaning typically used in the pharmaceutical formulation arts. As used herein, the term surfactant typically refers to the use of one or more surfactant, typically a non-ionic surfactant. Exemplary surfactants are described further herein.
  • terminal sterilized means, for example and without limitation, a physical method of sterilization once the formulations of the present invention are placed in a container that will be used to dispense such formulations for administration to a mammal, typically a human. Such methods include, for example, dry heat, steam, radiation and plasmas, with steam being typically used.
  • THC refers to a compound referred to as tetrahydrocannabinol and can include, for example, THC A, THCV, Delta-8 THC, and Delta-9 THC.
  • treatment contemplates partial or complete inhibition of a targeted medical indication, frequently the treatment of pain, when a composition of the present invention is administered prophylactically or following the onset of the medical indication, particularly pain, for which such pharmaceutical formulation of the present invention is administered.
  • the present invention provides a non-toxic parenteral pharmaceutical formulation comprising: i. at least one cannabinoid; ii. at least one surfactant; iii. at least one anti-oxidant; and iv. at least one chelating agent; and v. optionally, at least one buffering agent selected from the group consisting of hypotonic buffering agents and hypertonic buffering agents.
  • the present invention also provides a non-toxic parenteral pharmaceutical formulation comprising: i. at least one cannabinoid; ii. at least one surfactant; iii. at least one anti-oxidant; and iv. at least one chelating agent; and v. optionally, at least one buffering agent selected from the group consisting of hypotonic buffering agents and a hypertonic buffering agents; providing such formulation does not include an isotonic agent.
  • an additional aspect of the present invention provides a non-toxic parenteral pharmaceutical formulation comprising: i. at least one cannabinoid; ii. at least one surfactant; iii. at least two different anti-oxidants; and iv. at least one chelating agent; and v. optionally, at least one buffering agent selected from the group consisting of hypotonic buffering agents and hypertonic buffering agents.
  • the present invention further provides a non-toxic parenteral pharmaceutical formulation comprising: i. at least one cannabinoid; ii. at least one surfactant; iii. at least two different anti-oxidants; and iv. at least one chelating agent; and v. optionally, at least one buffering agent selected from the group consisting of hypotonic buffering agents and hypertonic buffering agents; providing such formulation does not include an isotonic agent.
  • the at least one cannabinoid as the active pharmaceutical ingredient, can be selected from the group consisting of, for example and without limitation, cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerolpropyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA) and other active constituents of the cannabis plant including, for example, each of the phytocannabinoids.
  • CBC cannabichromene
  • bioactive constituents include, for example and without limitation, cannabidiol -Cl (CBD-Cl ); cannabidio!-C4 (CBD-C4), and cannabidiol -C6 (CBD-C6).
  • bioactive metabolites such as, without limitation, 7-hydroxy CBD.
  • Such compounds and constituents can be derived from the cannabis plant, synthetically prepared, semi-synthetically prepared or as metabolites to one or more of such cannabinoids.
  • CBD cannabidiol
  • API active pharmaceutical ingredient
  • Plant-derived cannabinoids are available from a variety of United States and internationally-based suppliers that are readily identifiable through a simple internet search.
  • cannabidiol is a specialty chemical, available from limited producers.
  • cannabidiol API is available from Purisys LLC (Athens, Georgia, U.S.A.) and is used in the formulations described herein.
  • cannabidiol can be synthetically prepared, for example and without limitation, according to the teachings set forth in U.S. Pat. No. 10,059,683 (Noramco, Inc., Wilmington, Delaware, U.S.A., Assignee) and W02020/051371 (Noramco, Inc., Applicant).
  • the CBD used in the present formulations is the enantiomerically pure (-)- trans CBD form.
  • the cannabidiol used in the present formulation typically contains not more that 0.3% (-)-trans A 9 -tetrahydrocannabinol and, when possible, may be devoid of (-)-trans A 9 - tetrahydrocannabinol. Additionally, the cannabidiol used in the present formulation typically contains not more that 0.3% of any form of THC and, when possible, may be devoid of all forms of THC. More specifically, the API used in the present formulations contains not more than 0.3%, not more than 0.2%, not more than 0.1%, not more than 0.05%, not more than 0.01%, or any fraction thereof.
  • the concentration of total cannabinoid, particularly cannabidiol, used in the present formulation can vary in range including, for example and without limitation, at least 0.5 mg API per milliliter of final formulation solution. More particularly, such concentration ranges from about 0.5 to about 50 mg/mL and, more specifically, about 5 mg/mL, about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, and about 50 mg/mL of the final formulation solution, or any fraction or whole number within the stated range.
  • An additional element of the present formulations is the addition of at least one pharmaceutically acceptable surfactant, typically a non-ionic surfactant.
  • exemplary non-ionic surfactants include, for example and without limitation, polyoxyethylene (20) sorbitan monooleate, also called Polysorbate 80 (Tween 80) which is available from a multitude of supplier including, for example, Sigma-Aldrich/MilliporeSigma, (St. Louis, Missouri U.S.A.); Macrogol 15 hydroxystearate which is primarily a mixture of mono esters and di esters of 12-hydroxy stearic acid and macrogols obtained by the ethoxylation of 12-hydroxy stearic acid.
  • the number of moles of ethylene oxide reacted per mole of 12-hydroxy stearic acid is 15.
  • Proprietary versions of these surfactants include Solutol HS15 (MedChemExpress, Monmouth Junction, New Jersey U.S.A.), CrodasolTM HS (Croda Inc., Newark, New Jersey U.S.A.) and Kolliphor® HS 15 (BASF, Florham Park, New Jersey U.S.A.); and poloxamers which are triblock co-polymers of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene.
  • Polyoxamers are well known in the art and are available under the name “Pluronics”, and are readily supplied by a variety of suppliers found via an internet search.
  • Kolliphor HS 15 and/or Kolliphor ELP are frequently used in the present formulations.
  • Surfactant concentrations are used in the present formulations at a range from about 50 mg/mL to about 500mg/mL of final formulation solution. For example, when the desired cannabinoid concentration is about 10 mg/mL of final formulation solution, the concentration of surfactant is about 150 mg/mL of final formulation solution. As the concentration of cannabinoid is increased, so is the concentration of surfactant.
  • the concentration of surfactant is about 250 mg/mL of final formulation solution.
  • the ordinarily skilled artisan can further extrapolate the concentration of surfactant used in the present formulations based on the desired concentration of the desired at least one cannabinoid, typically cannabidiol. Additional exemplification is shown in Table 1 below.
  • the surfactant concentration in the present formulations can be about 50 mg/mL, about 100 mg/mL, about 150 mg/mL, about 200 mg/mL, about 250 mg/mL, about 300 mg/mL, about 350 mg/mL, about 400 mg/mL, about 450 mg/mL, about 500 mg/mL, or any whole or fractional number within the stated range of final formulation solution .
  • Antioxidants play an important role in the stability of the present formulations.
  • the same or different antioxidant is added to two separate process steps as described in more detail herein below.
  • the process comprises a first vessel into which the at least one cannabinoid, the at least one surfactant and a first at least one antioxidant are combined; and a second vessel into which the at least one chelating agent and at least one same or different antioxidant are combined, followed by the combination of materials from the first and second vessels to provide a final formulation solution, also referred to herein as the final formulation, notwithstanding the potential addition of optional ingredients unless such ingredient or ingredients are restricted from use herein.
  • the at least one antioxidant is added to reduce or eliminate the degradation of the at least one cannabinoid.
  • cannabidiol can rapidly degrade to a hydroxyquinone derivative, contaminating the formulation solution and reducing the desired concentration of cannabidiol in such solution formulation.
  • the absence of a purple tint to the formulation solution is a simple test for the absence of the hydroxy quinone degradation product.
  • the use of the same or different one or more antioxidant added to the second vessel further stabilizes the final formulation solution, generally in aqueous form, from oxidative degradation.
  • antioxidants are generally known to the skilled artisan in the pharmaceutical arts and include, for example and without limitation, the following classes of antioxidants: natural antioxidants including, for example, tocopherol (Vitamin
  • antioxidants including, for example, BHA, BHT, tertiary butyl hydroquinone
  • water-soluble antioxidant including, for example, citric acid, tartaric acid, phosphoric acid, ascorbic acid (and its precursors as delineated below), sodium metabisulfite and thiol derivatives
  • oil soluble antioxidant including, for example, BHA and BHT.
  • the antioxidants used are typically selected from the group consisting of the water-soluble antioxidants. More specifically, ascorbic acid, used in the form of ascorbyl palmitate, which hydrolyses, in part or in whole depending upon the composition in which the ascorbyl acid resides, to ascorbic acid, is typically used in the first vessel.
  • the same or different antioxidant is added to the second vessel can typically be ascorbic acid, ascorbyl palmitate, citric acid or combinations thereof although any appropriate antioxidant can be used in either the first or second vessel.
  • the concentration of the at least one pharmaceutically acceptable antioxidant typically comprises a total of from about 0.5 mg/mL of final formulation solution to about 10 mg/mL of final formulation solution, and more typically from about 1 mg/mL to about 5 mg/mL of final formulation solution. More specific antioxidant concentration are about 0.5 mg/mL, about 1.0 mg/mL, about 2.0 mg/mL, about 3.0 mg/mL, about 4.0 mg/mL, about 5.0 mg/mL, about 6.0 mg/mL, about 7.0 mg/mL, about 8.0 mg/mL, about 9.0 mg/mL, about 10.0 mg/mL, or any whole or fractional number within the stated range of final formulation solution. Such concentrations can be divided between the two preparatory vessels, frequently one-half of the total concentration of antioxidant in each vessel, using the same or different antioxidant in each vessel.
  • At least one pharmaceutically acceptable chelating agent represents an additional element of the present cannabinoid formulations of the present invention.
  • exemplary chelating agents include, for example and without limitation, eidetic acid (Spectrum Chemical Manufacturing Corp., New Brunswick, New Jersey U.S.A.), VerseneTM NA (Dow Chemical Company, Midland, Michigan, U.S.A., and EDTA (ethylenediaminetetraacetic acid; commonly available as disodium and calcium EDTA) and the like.
  • EDTA is readily available from a variety of sources found via a simple internet search.
  • the concentration of the at least one chelating agent in the present cannabinoid formulations typically is used in the range from about 0.1 mg/mL to about 5 mg/mL of final formulation solution. More specific chelating agent concentrations are about 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.0 mg/mL, 3.0 mg/mL, 4.0 mg/mL, 5.0 mg/mL, or any whole or fractional number within the stated range of final formulation solution. Typically, the concentration of such chelating agent as used in the present formulation is from about 0.5 mg/mL to about 3.0 mg/mL of final formulation solution.
  • a typical dosage of a chelating agent should not exceed 50 mg/Kg of body weight, and typically, not exceed 3 gm/day. These guidances need to be considered when formulating the formulations of the present invention to avoid toxicity from the chelating agent element of the present formulations.
  • the injection site can cause injection site irritation and pain.
  • a common reason for such irritation and pain is the pH of the solution being administered.
  • the pH of an intravenously (“IV”) administered formulation of the present invention can interfere with other administered medicaments, particularly those that are IV administered.
  • a buffered cannabinoid formulation of the present invention can reduce the injection site irritation and pain, particularly when administered as an infusion, and can provide an attending physician with a known, consistent pKa of a formulation of the present invention.
  • buffered solutions differ from isotonic saline in terms of three properties: lower sodium and chloride contents, bringing them closer to normal plasma levels; the presence of other ions such as potassium, calcium or magnesium, which could have effects on factors such as potassium or lactate levels, or could play a role in liver disease; and their contents of anions such as lactate, acetate and gluconate, which are metabolized to bicarbonate by tissue cells and may exert an additional buffering effect.
  • the concern for the addition of an at least one optional hypotonic or hypertonic buffering agent is the maintenance of solution pH at a predetermined point rather than a targeted isotonic osmolality of the final formulation solution.
  • an optional element of the present formulations is at least one hypotonic or hypertonic buffering agent.
  • buffering agents are well known in the pharmaceutical formulation development arts and include, for example and without limitation, at least one hypertonic or hypotonic (not isotonic) amount of at least one buffering agent, typically citric acid.
  • buffering agents typically citric acid.
  • other pharmaceutically acceptable buffers are known and used in liquid/aqueous pharmaceutical formulations. They include, for example and in addition to citric acid, bicarbonate buffers, carboxylic acid buffers, phosphate buffers, zwitterionic buffers, TRIS buffers and the like.
  • Each of such buffers when used with the present formulations, are used in an amount required to stabilize a formulation of the present invention at a pH from about 4.5 to about pH 6.0, and more typically between pH 5.0 and pH 5.5.
  • Non-isotonic amounts of, for example, citric acid are prepared by adding specific amount of citric acid to water, typically deionized water, or an aqueous solution such as the present formulations. Hypotonic or hypertonic solutions of citric acid, for example, can be readily prepared in a variety of concentrations. The amount used to buffer a formulation of the present invention will be determined by the strength of the buffer and the desired final buffered pH. Other buffers are similarly prepared and well known to the skilled artisan.
  • Further aspects of the present invention provide methods of preparing a formulation of the present invention: comprising: i. combining at least one surfactant with an at least one antioxidant and at least one cannabinoid to a first vessel; ii. combining at least one of the same or different second antioxidant and at least one chelating agent to a second vessel; and iii. combining the contents of the first and second vessels; and v. optionally adding at least one buffering agent selected from the group consisting of hypotonic buffering agents and hypertonic buffering agents.
  • the following is a non-limiting and exemplary preparation of the present formulations, using two vessels for the preparation of: i) a cannabinoid, particularly synthetically-prepared cannabidiol, a surfactant and an antioxidant; and ii) an antioxidant and a chelating agent, followed by combining the solutions of the two vessels:
  • Kolliphor HS 15 was heated to about 40°C (to allow it to become clear and molten for weighing)
  • Vessel B was rinsed with about 25% more WFI and the contents added to vessel A.
  • the present formulations are prepared as follows:
  • HS15 must be clear and warm when dispensing.
  • Vessel A should be set to process condition of about 50°C to about 70°C.
  • the melting point of CBD is about 65 to about 71 °C.
  • CBD API particle size will impact dissolution and slight variations of heating conditions may be required for complete dissolution of the CBD API
  • Citric acid addition to the Warm Kolliphor HS15 should prevent the solution from turning a purple color upon the addition of CBD.
  • Aqueous water phase is kept hot at the above-referenced temperature so that when it is added to Vessel A, solidification of Kolliphor HS15 containing CBD does not occur.
  • the ascorbic acid preparation typically should not be premade.
  • Using a mixer or a glass rod ensures to hydrate any Kolliphor HS15 off the sides of the vessel and gets into solution the desired concentrations of each formulation element.
  • the solution may turn hazy as water is added; this is due to the formed micelles being larger and visible to the naked eye at elevated temperatures. As the final formulation solution is brought to final volume, the solution will turn less hazy and typically turn completely clear when reaching ambient temperature. As such, water is added to the formulation as desired or predetermined to meet the concentration requirements set forth herein for each element of the present formulations.
  • tubing should be platinum cured to prevent CBD adsorption onto tubing.
  • any bubbles are dissipated prior to filling vials or another final container for the present formulations. Filling into vials or such other containers should be conducted by weight using density of the formulation followed by an inert gas sparge to remove any dissolved oxygen.
  • the ratios for the table result in a clear liquid when Q.S. with water for injection.
  • CBD concentration e.g., with 250 mg/mL
  • the ratio of surfactant to cannabidiol is from about 0.1 to about 20 mg/mL, while maintaining stability.
  • the present invention provides non-toxic formulations that are administered via at least one parenteral (intravenous (IV), intramuscular (IM) and intraperitoneal (IP) means of administration.
  • IV parenteral
  • IM intramuscular
  • IP intraperitoneal
  • dosage forms including, for example and without limitation, one or more vials, ampules, syringes, infusion bags or other pharmaceutically acceptable containers filled with a formulation of the present invention.
  • Such dosage forms may be single or multiple use dosage forms.
  • such dosage forms may be prepared with an inert gas headspace to assist in preventing oxidation and/or degradation of the API which is typically indicated by a change of color of the present formulations.
  • inert gas can include, typically, nitrogen and argon.
  • longer headspace vials topped-off with such inert gas may provide additional long-term stability of the present formulations.
  • the glass or plastic dosage forms referenced above may by amber or dark colored to ensure against any photodegradation.
  • a given dosage form or bulk formulation can typically be maintained at ambient temperature.
  • dosage forms, or bulk formulation may also be stored under non-freezing, refrigerated conditions.
  • the present formulations may also be freeze dried that typically requires the addition of a pharmaceutically acceptable bulking agent such as mannitol, lactose, sucrose, dextran, glycerin and/or trehalose.
  • a pharmaceutically acceptable bulking agent such as mannitol, lactose, sucrose, dextran, glycerin and/or trehalose.
  • the bulking agents also provide cryoprotection to the product. Concentrations of added bulking agents are frequently dependent upon the nature and amount of other ingredients in the formulation. Such concentrations are known to the skilled artisan.
  • the present pharmaceutical formulations are stable for a period of at least six months to at least 2 years, or any whole or fractional number withing or exceeding this range. More specifically, the present formulations, in bulk form or, more particularly, in dosage form ready for use in administering the present formulations, are stable for about 6 months, about 1 year, about 1.5 years, about 2 years, or a whole or fractional number within the range of about 6 months to about 2 years, generally without refrigeration. Typically, it is desirable for the present formulation to be stable and usable for a period of at least two years following preparation of the present formulations and filled into one or more appropriate container.
  • Another aspect of the present invention provides a formulation of the present invention that can be terminally sterilized.
  • Such sterilization can be completed by any method presently known or developed in the future that can provide a sterilized formulation of the present invention once such formulation is placed into a container, typically a container that will be used to dispense such formulations for administration to a mammal, typically a human.
  • Such methods include, for example, dry heat, steam, radiation and plasmas, with steam being typically used.
  • sterile pharmaceutical formulations can be utilized such as, for example and without limitation, gases such as ethylene oxide, glutaraldehyde, propylene oxide, hydrogen peroxide and chlorine dioxide, sterile filtration and preparation of the present formulations under aseptic manufacturing conditions such as designed with appropriate pore sizes/surface chemistries that remove bacteria and other microorganisms via size exclusion, entrapment, electrostatic attraction and other modalities.
  • gases such as ethylene oxide, glutaraldehyde, propylene oxide, hydrogen peroxide and chlorine dioxide
  • sterile filtration and preparation of the present formulations under aseptic manufacturing conditions such as designed with appropriate pore sizes/surface chemistries that remove bacteria and other microorganisms via size exclusion, entrapment, electrostatic attraction and other modalities.
  • present formulations can be compounded with other medicaments, fluids or other constituents typically used for parenteral administration.
  • a cannabinol pharmaceutical formulation of the present invention prepared on or in a patch for the transdermal delivery of such pharmaceutical formulation.
  • patches are known in the art and include for example, reservoir and rate-controlling membrane patches, matrix patches, active pharmaceutical ingredient in adhesive patches, electroporation, iontophoresis, sonophoresis and microneedle patches.
  • a method of delivering a pharmaceutical formulation of the present invention via one or more pharmaceutically acceptable patch delivery systems may not be optimal for adequate delivery of the present pharmaceutical formulations requiring additional research and development to accomplish the desired dosage strength.
  • patches can be used for the treatment of the disease states treatable by the parenteral formulation set forth herein and can be used as a single treatment or sequentially before, with or following one or more parenteral administrations of the parenteral pharmaceutical formulations set forth herein.
  • the present invention further provides a method of treating a mammal, typically a human, in need of treatment comprising parenteral administration, typically intravenous administration, of a formulation of the present invention.
  • parenteral administration typically intravenous administration
  • the medical and/or pharmaceutical use of the present formulations are not limited by exemplification as a multitude of potential medical maladies can be treated via parenteral administration, frequently via IV administration, of the formulations of the present invention.
  • One such use includes, for example and without limitation, parenteral admiration, typically IV administration, of a formulation of the present invention to treat pain selected from the group consisting of peri-operative pain, post-operative pain and combinations thereof or, in other words, for peri-and/or post-operative pain management.
  • pain and, thus need for treatment, can be evaluated as mild, mild to moderate, moderate, moderate to severe, severe, or other pain as described by a patient in need of treatment on any one of various pain scales used by the medical community.
  • Pain rating scales are used in daily clinical practice to measure pain intensity.
  • the commonly used measurement scales include the Visual Analog Scale (VAS), the Graphic Rating Scale (GRS), the Simple Descriptor Scale (SDS), the Numerical Rating Scale (NRS), and the Faces Rating Scale (FRS). All of these scales have been documented as being valid measures of pain intensity.
  • the three scales most commonly used in the U.S. are the numerical, word and faces scales.
  • the present formulations can be used, for example, to treat acute or chronic pain, including, for example, neuropathic pain and/or pain associated with certain forms of cancer, whether pari- operative pain or otherwise, in a hospital, clinic, home, military or other setting when administered and monitored by appropriate, typically, medical, personnel.
  • the present formulations can be used to treat pain as described within the pain matrix (also known as the neuromatrix) including, for example and without limitation, pain associated with a variety of different pain syndromes including such conditions as fibromyalgia, phantom limb pain, post-herpetic neuralgia, complex regional pain syndromes (CRPS), diabetic neuropathy, and central pain related to stroke or spinal cord injuries.
  • the pain matrix also known as the neuromatrix
  • the pain matrix also known as the neuromatrix
  • pain associated with a variety of different pain syndromes including such conditions as fibromyalgia, phantom limb pain, post-herpetic neuralgia, complex regional pain syndromes (CRPS
  • the methods of using the present formulations further include, for example, the treatment of pain in soft and boney tissues, pain related to trauma and, generally, any form of pain for which opioid drugs are presently used whether administered orally or via parenteral administration.
  • the present formulations, particularly when administered as infusions, may also be used in special occasions for the treatment of severe depression and refractory headaches.
  • the formulations of the present invention can also be used to treat Dravet Syndrome, Lennox Gastaut Syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, tuberous sclerosis complex, brain tumors, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, neurodegenerative diseases such as Alzheimer's Disease and Parkinsonism, and autism. More particularly, the epilepsy uses of the present pharmaceutical formulations are typically used for emergency use.
  • inflammatory diseases including cardiac inflammatory diseases such as pericarditis and endocarditis, high blood pressure and other disease states treated by a vasorelaxant, arrythmia, congestive heart failure, arterial plaque (and the reduction thereof), reducing glucose absorption from arterial walls, inhibiting endotoxin production, stroke (pre-, during and post- a stroke occurrence and, generally, by providing cerebroprotection and cerebrorecovery; treatment of ischemic and hemorrhagic stroke).
  • cardiac inflammatory diseases such as pericarditis and endocarditis
  • high blood pressure and other disease states treated by a vasorelaxant arrythmia
  • congestive heart failure reducing arterial plaque (and the reduction thereof)
  • reducing glucose absorption from arterial walls inhibiting endotoxin production
  • stroke pre-, during and post- a stroke occurrence and, generally, by providing cerebroprotection and cerebrorecovery; treatment of ischemic and hemorrhagic stroke.
  • the present formulations can be prepared in a variety of dosage forms include, for example, vials, ampules, syringes, infusion bag or other pharmaceutically acceptable container.
  • dosage forms can be filled with one of a variety of dosage concentrations of cannabinoid, typically cannabidiol, as used in the present formulations.
  • cannabinoid typically cannabidiol
  • dosage forms are filled with a formulation of the present invention comprising at least 0.5 mg cannabinoid, typically cannabidiol, per milliliter of final formulation solution.
  • such concentration ranges from about 0.5 mg/mL to about 50 mg/mL and, more specifically, about 5 mg/mL, about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL and about 50 mg/mL of the final formulation solution, or any fraction or whole number within the stated range.
  • Certain dosage forms such as, for example, syringes, containing the present formulations can be directly administered or injected into a bolus or infusion bag containing any one of a multitude of pharmaceutically acceptable fluids that may be administered to a patient.
  • Such fluids can include, for example and without limitation, nutrients, hydrating fluids and/or other treatments for pain, other maladies and/or any other medical purposes.
  • a small amount of the present formulation should be premixed with the other such fluid or fluids to ensure compatibility of the mixture prior to administration.
  • Formulations of the present invention can be presented in other pharmaceutically acceptable containers that can be used to prepare final forms for bolus or infusion administration, frequently slow infusion over a period of time.
  • such formulation is typically administered in one to two doses pre- operatively, and another one to two doses post-operatively.
  • the actual number of doses, dosage concentration and timing of doses is typically left to the discretion of the attending physician, physician assistant, medic and the like. Accordingly, the dosage amount, number of doses and timing of such doses is not intended to be limited by the present disclosure.
  • Dosages of the present formulation should be calculated on the amount of API, typically cannabidiol, on a mg/Kg basis wherein such dosage should be in the range of about 0.1 mg/Kg to about 10 mg/Kg. More particularly, such dosages include, for example, 0.1 mg/Kg, 0.5 mg/Kg, 1.0 mg/Kg, 2.0 mg/Kg, 3.0 mg/Kg, 4.0 mg/Kg, 5.0 mg/Kg, 6.0 mg/Kg, 7.0 mg/Kg, 8.0 mg/Kg, 9.0 mg/Kg, 10.0 mg/Kg, greater than 10.0 mg/Kg, or any other whole or fractional number within the stated range.
  • HPLC analytical method An Agilent 1200 series HPLC system consisting of a quaternary gradient pump, autosampler, column oven, and a single wavelength detector (UV-vis) was used to analyze CBD.
  • the detector wavelength was set at 220 nm.
  • the chromatographic separations were performed at 35 °C temperature on a Hichrom C18 reverse phase column ((150 x 4.5 mm), 4.7 pm).
  • the mobile phase was a mixture of Acetonitrile: 0.25% Acetic Acid: Methanol (75:20:5, v/v), filtered and flowing at the rate of 1 mL/min. The data was collected and analyzed.
  • Stock solution (1.0 mg/mL) of CBD was prepared by dissolving 50 mg CBD in 50 mL HPLC grade methanol using a 50 mL volumetric flask. Then calibration standard solutions of 25, 50, 100, and 250 pg/mL of CBD were prepared by diluting the stock solutions into HPLC grade methanol.
  • Samples were prepared at a concentration of 0.1 mg/mL in methanol and injected onto the system.
  • This stability study was conducted on 1 batch of 10 mg/mL CBD intravenous formulation.
  • the development batch used was manufactured at a proposed clinical scale of 1 L manufactured lots.
  • the batch was sub-divided to provide sufficient samples for the different storage conditions and time-points.
  • a placebo was also set alongside this study if required at the timepoints.
  • shelf-life and storage conditions of the IMP should be defined based on the stability profile of the active substance and the available data on the IMP. Extrapolation may be used, provided that stability studies are conducted in parallel to the clinical studies and throughout its entire duration.
  • a fourfold extrapolation of real time data may be acceptable up to a shelf life of 12 months and an extrapolation of x+12 months for a shelf life of more than 12 months.
  • the manufacture can take place in a single vessel using a heated jacketed mixer vessel.
  • To the vessel add the antioxidant and continue mixing until dissolved.
  • Using a liquid feeder dispense the pre-warmed water phase containing the antioxidants, buffering agents and chelating agents and mix altogether within the mixer vessel. Once mixed, set the jacketed vessel to cool down to room temperature.
  • On the outlet valve conduct a bioburden reduction filter prior to aseptic fill and nitrogen flush finish of the product.

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